Actions of adenosine A 1 and A 2 receptor antagonists on CFTR antibody‐inhibited β ‐adrenergic mucin secretion response

1 The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3‐isobutyl‐1‐methylxanthine (IBMX) corrects the defect in CFTR mediated β‐adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A 1 and A 2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited β‐adrenergic response and whether excessive cyclic AMP rise is required. 2 CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured. 3 The adenosine A 1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A 2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the K i for A 1 receptor antagonism (10 n M ) did not stimulate mucin secretion. 4 DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion. 5 CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 m M ) concentration, suggesting a mechanism other than adenosine receptor antagonism. 6 DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not. 7 Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of β‐adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis.British Journal of Pharmacology (1998) 125 , 697–704; doi: 10.1038/sj.bjp.0702128